The invention relates to methods for esterifying alcohols. In particular, the invention provides novel compounds and methods useful in the production of Taxol and Taxol analogs.
The esterification of alcohols is a common reaction in organic synthesis. Once the ester is produced, the ester can undergo further reactions to produce complex molecules. This approach is especially significant in the synthesis of natural products and non-natural synthetic compounds that exhibit biological activity. By converting a hydroxyl group to an ester, the chemical properties of the compound can change dramatically. An example of this improved property is the anti-cancer drug, Taxol.
Taxol and other antitumor taxoids constitute some of the most important discoveries in cancer chemotherapy in recent years. Taxol and Taxotere, which is a semi-synthetic analog of Taxol, have been approved by the FDA for the treatment of advanced ovarian and breast cancer. Additionally Taxol and Taxotere may be useful for the treatment of non-small-cell lung cancer, head and neck cancer and several other cancers. The structures of Taxol and Taxotere are shown below. 
Taxol and Taxotere differ in their structure at the C-10 and C-3=positions. While Taxol was first isolated from the bark of the pacific yew tree, Taxus brevifola, Taxotere, a synthetic analog of Taxol, possesses better bioavailability than Taxol. Due to the limited availability of Taxol from the yew tree (1 Kg from 10000 Kg of bark), different strategies including total synthesis, semisynthesis, cell and tissue culture of taxus spp., have been investigated so that large amounts of Taxol can be produced. Although the total synthesis of Taxol was accomplished in 1994, lengthy multi-step sequences led to poor overall yield of Taxol. Therefore, total synthesis has not to date been a viable alternative to solve the supply problem.
One approach to a large scale production of Taxol and Taxotere is their semisynthesis from 10-deacetyl baccatin III (referred to as baccatin III or baccatin), shown below. Baccatin III can be readily obtained from the needles of the yew tree Taxus baccata. Importantly, yew needles can be quickly regenerated; therefore, a continuous supply of Taxol may be available without affecting the yew population. 
Structure-activity relationships of Taxol derivatives indicate that the C-13 N-benzoyl-3-phenyl isoserine side chain, with the 2xe2x80x2R, 3xe2x80x2S stereochemistry, is of crucial importance for Taxol""s cytotoxicity. Although there are methods in the art for the asymmetric synthesis of the C-13 side chain, coupling the side chain to the C-13 hydroxyl group is not a simple endeavor. The coupling reaction is complicated by the fact that the C-13 hydroxyl group is situated in the skeletal concavity of baccatin III, which makes this hydroxyl group sterically hindered. Furthermore, the C-13 hydroxyl group has been proposed to form a stabilizing hydrogen bond with the C-4 acetate moiety. These two factors contribute to the difficulty encountered in attaching the side chain to the C-13 hydroxyl group.
One approach to attaching the isoserine side chain to the C-13-hydroxyl group involves a condensation reaction between baccatin and an isoserine acid. Greene et al. (J. Ami. Chem. Soc. 1988, 110, 5917) discloses the direct esterification reaction of a protected form of baccatin III and an isoserine acid under vigorous conditions (73xc2x0 C. for 4 days). International Patent Application No. WO 94/18186 to Swindell et al.; U.S. Pat. No. 5,675,025 to Sisti et al.; and U.S. Pat. No. 5,597,931 to Danishefsky et al. also disclose the condensation reaction between protected baccatins and isoserine acids and esters.
Another approach involves the condensation reaction between a heterocycle containing a carboxylic acid group and baccatin, followed by treatment with an acid to open the ring and produce the side chain at C-13. Kingston et al. (Tetrahedron Letters 1994, vol 35, no. 26, pp 4483) and International Patent Application No. WO 97/00870 to Gennari et al. disclose the coupling of oxazolidines and baccatin via a condensation reaction. U.S. Pat. No. 5,599,942 to Bouchard et al.; International Patent Application No. WO 94/10169 to Denis et al.; International Patent Application No. WO 94/10169; and Kanazawa et al. (J. Chem. Chem. Com. 1994, 2591) disclose the coupling of a 1,3-oxazole with baccatin followed by acid hydrolysis produced Taxol and derivatives thereof. In the respective condensation reactions disclosed in the above-identified patents and articles, the stereochemistry at C-2 of the heterocycle, wherein C-2 is the carbon bonded to the carboxylic acid group, has to be established (either S or R stereochemistry).
Gennari et al. (Angew. Chem. Int. Ed. Engl. 1996, 35, 1723) discloses the reaction between a protected baccatin and a thioester of an oxazolidine in the presence of a base. In the case of the oxazolidine, seven steps were required to produce the oxazolidine with the thioester group, wherein the first step involves the use of chiral boron agent. The resulting oxazolidine thioester produced and subsequently coupled with baccatin is the anti isomer and not the syn isomer. The coupling reaction involves adding a base to a mixture of the protected baccatin and the oxazolidine thioester. An excess of oxazolidine thioester (3.5 equivalents) and base (4.5 equivalents) are used in the coupling reaction. Similar to the condensation reactions described above, the stereochemistry at C-2 of the oxazolidine thioester is also established.
Therefore, there remains a need for a more efficient, high yield synthesis of Taxol and other similar compounds. In addition, there exists a need for synthetic methods where the stereochemistry at C2 of the precursor to the side chain does not have to be established.
To overcome the shortcomings described above, the present invention, in one aspect, relates to a method for preparing an ester, comprising:
(a) admixing a compound having the structure I: 
xe2x80x83wherein,
R1 and R2 are, independently, from C1 to C12 branched or straight chain alkyl; or substituted or unsubstituted aryl; and
X is a halogen or OR3, wherein R3 is from C1 to C12 branched or straight chain alkyl; substituted or unsubstituted aryl; aralkyl; acyl, or S(O)2R41, wherein R41 is C1 to C12 branched or straight chain alkyl; or substituted or unsubstituted aryl,
xe2x80x83with a base to form an intermediate; and
(b) admixing the intermediate of step (a) with an alcohol, an alkoxide, or a combination thereof.
The invention further relates to a method for preparing an ester, comprising admixing a compound having the structure III: 
wherein,
R1 and R2 are, independently, from C1 to C12 branched or straight chain alkyl or substituted or unsubstituted aryl,
with an alcohol, an alkoxide or a combination thereof.
The invention further relates to a method for preparing an ester, comprising admixing:
(a) a base;
(b) an alcohol, an alkoxide or a combination thereof; and
(c) a compound having the structure I: 
xe2x80x83wherein,
R1 and R2 are, independently, from C1 to C12 branched or straight chain alkyl; or substituted or unsubstituted aryl; and
X is a halogen or OR3, wherein R3 is from C1 to C12 branched or straight chain alkyl; substituted or unsubstituted aryl; aralkyl; acyl, S(O)2R41, wherein R41 is C1 to C12 branched or straight chain alkyl; or substituted or unsubstituted aryl.
The invention further relates to a method for preparing an ester, comprising admixing:
(a) a base;
(b) an alcohol, an alkoxide or a combination thereof; and
(c) a compound having the structure IV: 
xe2x80x83wherein,
R9 and R10 are, independently, an aralkyl or C(O)R31, wherein R31 is C1 to C12 straight chain or branched alkyl; substituted or unsubstituted aryl; or aralkyl;
R11 is from C1 to C12 branched or straight chain alkyl or substituted or unsubstituted aryl;
R12 is silyl, alkyl, acyl, aryl, or aralkyl; and
Y is a halogen or OR13, wherein R13 is from C1 to C12 branched or straight chain alkyl; or substituted or unsubstituted aryl; aralkyl; acyl; or S(O)2R42, wherein R42 is C1 to C12 straight chain or branched alkyl; or substituted or unsubstituted aryl.
The invention further relates to a method for preparing an ester, comprising admixing:
(a) an alcohol, an alkoxide, or a combination thereof; and
(b) a compound having the structure V: 
xe2x80x83wherein,
R9 and R10 are, independently, an aralkyl or C(O)R31, wherein R31 is C1 to C12 straight chain or branched alkyl; substituted or unsubstituted aryl; or aralkyl;
R11 is from C1 to C12 branched or straight chain alkyl or substituted or unsubstituted aryl; and
R12 is silyl, alkyl, aryl, aralkyl or acyl.
The invention further relates to a method for preparing a compound having the structure I: 
xe2x80x83wherein,
R1 and R2 are, independently, from C1 to C12 branched or straight chain alkyl or substituted or unsubstituted aryl; and
X is OR3, wherein R3 is from C1 to C12 branched or straight chain alkyl; substituted or unsubstituted aryl; aralkyl; acyl, or S(O)2R41, wherein R41 is C1 to C12 branched or straight chain alkyl; or substituted or unsubstituted aryl, and
R2 and C(O)X are cis to one another,
comprising:
(a) admixing a compound having the structure VI: 
xe2x80x83wherein,
R1 and R2 are, independently, from C1 to C12 branched or straight chain alkyl or substituted or unsubstituted aryl;
X is OR3, wherein R3 is from C1 to C12 branched or straight chain alkyl; substituted or unsubstituted aryl; aralkyl; acyl, or S(O)2R41, wherein R41 is C1 to C12 branched or straight chain alkyl; or substituted or unsubstituted aryl; and
the hydroxyl group and amide group are cis to one another, with a cyclization agent.
The invention further relates to a compound having the formula I: 
xe2x80x83wherein,
R1 and R2 are, independently, from C1 to C12 branched or straight chain alkyl or substituted or unsubstituted aryl;
X is OR3, wherein R3 is halogen; C1 to C12 branched or straight chain alkyl; substituted or unsubstituted aryl; aralkyl; acyl, aralkyl, or S(O)2R41, wherein R41 is C1 to C12 branched or straight chain alkyl; or substituted or unsubstituted aryl; and
R2 and C(O)X are cis to one another.
The invention further relates to a compound having the structure IV: 
xe2x80x83wherein,
R9 and R10 are aralkyl;
R11 is substituted or unsubstituted aryl;
R12 is acyl, silyl, alkyl, aryl or aralkyl; and
Y is a halogen or OR13, wherein R13 is from C1 to C12 branched or straight chain alkyl; substituted or unsubstituted aryl, acyl, aralkyl or S(O)2R42, wherein R42 is C1 to C12 branched or straight chain alkyl; or substituted or unsubstituted aryl.
The invention further relates to a method for preparing a compound having the structure IV: 
wherein,
R9 and R10 are aralkyl;
R11 is substituted or unsubstituted aryl;
R12 is acyl, silyl, alkyl, aryl, or aralkyl; and
Y is OR13, wherein R13 is from C1 to C12 branched or straight chain alkyl; substituted or unsubstituted aryl; acyl, aralkyl, or S(O)2R42, wherein R42 is C1 to C12 branched or straight chain alkyl or substituted or unsubstituted aryl,
comprising:
(a) admixing a base and a compound having the structure IX: 
xe2x80x83wherein,
R9 and R10 are aralkyl;
R11 is substituted or unsubstituted aryl; and
Y is OR13, wherein R13 is from C1 to C12 branched or straight chain alkyl; or substituted or unsubstituted aryl, acyl, aralkyl, or S(O)2R42, wherein R42 is C1 to C12 branched or straight chain alkyl; or substituted or unsubstituted aryl,
to produce an intermediate, and
(b) admixing the intermediate of step (a) with an esterification agent, a silylating agent, or an alkylating agent.
The invention further relates to a method for preparing an ester, comprising admixing a compound having the structure VII: 
wherein,
R15 and R16 are, independently, hydrogen, Si(R21)3 or C(O)R22, wherein each R21 is, independently, branched or straight chain C1-C12 alkyl; and R22 is substituted or unsubstituted aryl, aralkyl or from C1-C12 branched or straight chain alkyl;
R17 is substituted or unsubstituted aryl, aralkyl, or from C1-C12 branched or straight chain alkyl;
R18 is hydrogen; branched or straight chain C1-C12 alkyl; unsubstituted or substituted aryl; aralkyl; Si(R28)3 or C(O)R29, wherein, each R28 is, independently, branched or straight chain C1-C12 alkyl; or aralkyl;
R29 is substituted or unsubstituted aryl, aralkyl or from C1-C12 branched or straight chain alkyl;
R19 and R20 are, independently, branched or straight chain C1-C12 alkyl, aryl, aralkyl, or C(O)OR30, wherein R19 is not hydrogen;
R30 is branched or straight chain C1-C12 alkyl; and
V and W are, independently, sulfur, oxygen, or NR43, wherein R43 is hydrogen; branched or straight chain C1-C12 alkyl; or aralkyl,
with an alkoxide.
The invention further relates to a method for preparing a compound having the structure VII: 
wherein,
R15 and R16 are, independently, hydrogen, Si(R21)3 or C(O)R22, wherein each R21 is, independently, branched or straight chain C1-C12 alkyl; and R22 is substituted or unsubstituted aryl, aralkyl or from C1-C12 branched or straight chain alkyl;
R17 is substituted or unsubstituted aryl, aralkyl, or from C1-C12 branched or straight chain alkyl;
R18 is branched or straight chain C1-C12 alkyl; unsubstituted or substituted aryl; aralkyl; Si(R28)3 or C(O)R29, wherein,
each R28 is, independently, branched or straight chain C1-C12 alkyl; or aralkyl;
R29 is substituted or unsubstituted aryl, aralkyl or from C1-C12 branched or straight chain alkyl;
R19 and R20 are, independently, branched or straight chain C1-C12 alkyl, aryl, aralkyl, or C(O)OR30, wherein R19 is not hydrogen;
R30 is branched or straight chain C1-C12 alkyl; and
V and W are, independently, sulfur, oxygen, or NR43, wherein R43 is hydrogen; branched or straight chain C1-C12 alkyl; or aralkyl,
comprising,
(a) admixing
(i) a compound having the structure X 
wherein R18-R20 are as above,
(ii) a Lewis acid; and
(iii) a base,
to produce a first intermediate;
(b) reacting the first intermediate of step (a) with a compound having the structure XI: 
wherein R15 and R17 are as above,
to produce a second intermediate; and
(c) admixing the second intermediate of step (b) with a proton source.
The invention further relates to a compound having the structure VII: 
wherein,
R15 and R16 are, independently, hydrogen, Si(R21)3 or C(O)R22, wherein each R21 is, independently, branched or straight chain C1-C12 alkyl; and R22 is substituted or unsubstituted aryl, aralkyl or from C1-C12 branched or straight chain alkyl;
R17 is substituted or unsubstituted aryl, aralkyl, or from C1-C12 branched or straight chain alkyl;
R18 is hydrogen; branched or straight chain C1-C12 alkyl; unsubstituted or substituted aryl; aralkyl; Si(R28)3 or C(O)R29, wherein,
each R28 is, independently, branched or straight chain C1-C12 alkyl; or aralkyl;
R29 is substituted or unsubstituted aryl, aralkyl or from C1-C12 branched or straight chain alkyl;
R19 and R20 are, independently, branched or straight chain C1-C12 alkyl, aryl, aralkyl, or C(O)OR30, wherein R19 is not hydrogen;
R30 is branched or straight chain C1-C12 alkyl; and
V and W are, independently, sulfur, oxygen, or NR43, wherein R43 is hydrogen; branched or straight chain C1-C12 alkyl; or aralkyl.
The invention further relates to a method for preparing a compound having the structure VII: 
wherein,
R15 and R16 are, independently, hydrogen, Si(R21)3 or C(O)OMe, wherein each R21 is, independently, branched or straight chain C1-C12 alkyl; and R22 is substituted or unsubstituted aryl, aralkyl or from C1-C12 branched or straight chain alkyl;
R17 is substituted or unsubstituted aryl, aralkyl, or from C1-C12 branched or straight chain alkyl;
R18 is hydrogen:
R19 and R20 are, independently, branched or straight chain C1-C12 alkyl, aryl, aralkyl, or C(O)OR30, wherein R19 is not hydrogen;
R30 is branched or straight chain C1-C12 alkyl; and
V and W are, independently, sulfur, oxygen, or NR43, wherein R43 is hydrogen; branched or straight chain C1-C12 alkyl; or aralkyl,
comprising,
(a) admixing
(i) a compound having the structure XIII 
wherein R19-R20 and R22 are as above,
(ii) a Lewis acid; and
(iii) a first base,
to produce a first intermediate;
(b) reacting the first intermediate of step (a) with a compound having the structure XI: 
wherein R15 and R17 are as above,
to produce a second intermediate; and
(c) admixing the second intermediate with a basic buffer, wherein the buffer comprises a second base.
The invention further relates a compound having the structure XIV or XV: 
wherein,
R44 and R45 are, independently, hydrogen; C1-C12 branched or straight chain alkyl; or R44 and R45 are part of a cycloaliphatic group;
when g is a single bond, R46 is hydroxy; acetyl; or C1-C12 branched or straight chain alkoxy;
when g is a double bond, R46 is oxygen;
R47 is a C1-C12 branched or straight chain alkyl ester; C1-C12 branched or straight chain alkyl; carboalkoxy; hydroxyalkyl; or derivatized or protected hydroxyalkyl;
R48 is C1-C12 branched or straight chain alkyl; substituted or unsubstituted aryl; acetyl; hydroxyalkyl; or derivatized or protected hydroxyalkyl;
R49 and R50 are, independently, hydrogen; C1-C12 branched or straight chain alkyl or alkoxy; or acetyl, provided that when one of R49 or R50 is hydrogen, the other of R49 and R50 is not hydrogen;
when m is a double bond, R51 is oxygen;
when m is a single bond, R51 is OH or OC(O)R52, wherein R52 is substituted or unsubstituted aryl; or cycloaliphatic; and
the hydroxyl group is located at carbon h or i.
None of the references described above disclose the methods and compounds of the present invention. Additional advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention. The advantages of the invention will be realized and attained by means of the elements and combinations particularly pointed out in the appended claims. It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed.
The present invention may be understood more readily by reference to the following detailed description of preferred embodiments of the invention and the examples included therein.
Before the present compositions of matter and methods are disclosed and described, it is to be understood that this invention is not limited to specific synthetic methods or to particular formulations, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.
In this specification and in the claims which follow, reference will be made to a number of terms which shall be defined to have the following meanings:
The singular forms xe2x80x9ca,xe2x80x9d xe2x80x9canxe2x80x9d and xe2x80x9cthexe2x80x9d include plural referents unless the context clearly dictates otherwise.
Throughout the application, the term xe2x80x9ccompoundxe2x80x9d refers to all compounds embodied by the designated structure in the present application. For example, compound I refers to all compounds having the structure I as defined in the application.
The term xe2x80x9caralkylxe2x80x9d is defined as any group that has one or more aliphatic or cycloaliphatic groups attached to an aromatic ring.
The term xe2x80x9ccyclization agentxe2x80x9d is defined as an agent that activates a hydroxyl group and renders the carbon attached to it more susceptible to internal nucleophilic attack.
The term xe2x80x9cesterification agentxe2x80x9d is defined as any agent that will catalyze the formation of an ester from an alcohol or alkoxide and a carboxylic acid.
Esterification of Alcohols-Part I
In accordance with the purpose(s) of this invention, as embodied and broadly described herein, this invention, in one aspect, relates to a method for preparing an ester, comprising:
(a) admixing a compound having the structure I: 
xe2x80x83wherein,
R1 and R2 are, independently, from C1 to C12 branched or straight chain alkyl; or substituted or unsubstituted aryl; and
X is a halogen or OR3, wherein R3 is from C1 to C12 branched or straight chain alkyl; substituted or unsubstituted aryl; aralkyl; acyl, or S(O)2R41, wherein R41 is C1 to C12 branched or straight chain alkyl; or substituted or unsubstituted aryl,
xe2x80x83with a base to form an intermediate; and
(b) admixing the intermediate of step (a) with an alcohol, an alkoxide, or a combination thereof.
The invention further relates to a method for preparing an ester, comprising admixing a compound having the structure III: 
wherein,
R1 and R2 are, independently, from C1 to C12 branched or straight chain alkyl or substituted or unsubstituted aryl,
with an alcohol, an alkoxide or a combination thereof.
The invention further relates to a method for preparing an ester, comprising admixing:
(a) a base;
(b) an alcohol, an alkoxide or a combination thereof, and
(c) a compound having the structure I: 
xe2x80x83wherein,
R1 and R2 are, independently, from C1 to C12 branched or straight chain alkyl; or substituted or unsubstituted aryl; and
X is a halogen or OR3, wherein R3 is from C1 to C12 branched or straight chain alkyl; substituted or unsubstituted aryl; aralkyl; acyl, or S(O)2R41, wherein R41 is C1 to C12 branched or straight chain alkyl; or substituted or unsubstituted aryl.
The invention further relates to a method for preparing an ester, comprising admixing:
(a) a base;
(b) an alcohol, an alkoxide or a combination thereof; and
(c) a compound having the structure IV: 
xe2x80x83wherein,
R9 and R10 are, independently, an aralkyl or C(O)R31, wherein R31 is C1 to C12 straight chain or branched alkyl; substituted or unsubstituted aryl; or aralkyl;
R11 is from C1 to C12 branched or straight chain alkyl or substituted or unsubstituted aryl;
R12 is silyl, alkyl, acyl, aryl, or aralkyl; and
Y is a halogen or OR13, wherein R13 is from C1 to C12 branched or straight chain alkyl; substituted or unsubstituted aryl; aralkyl; acyl; or S(O)2R42, wherein R42 is C1 to C12 straight chain or branched alkyl; substituted or unsubstituted aryl
The invention further relates to a method for preparing an ester, comprising admixing:
(a) an alcohol, an alkoxide, or a combination thereof; and
(b) a compound having the structure V: 
xe2x80x83wherein,
R9 and R10 are, independently, an aralkyl or C(O)R31, wherein R31 is C1 to C12 straight chain or branched alkyl; substituted or unsubstituted aryl; or aralkyl;
R11 is from C1 to C12 branched or straight chain alkyl or substituted or unsubstituted aryl; and
R12 is silyl, alkyl, aryl, aralkyl or acyl.
The applicants have discovered that the combination of a base, an alcohol, and compound I or IV results in the formation of an ester. In one embodiment, the base can be added to a mixture of the alcohol and compound I and IV. In a preferred embodiment, compound I or IV is treated with a base, followed by the addition of the alcohol.
Without wishing to be bound by theory, it is believed that when the base and compound I or IV are combined together, the ketene complexes III and V are produced, respectively. It is believed that the base deprotonates a hydrogen at the xcex1-carbon (the carbon adjacent to the C(O)X group) of I and IV with concomitant loss of the leaving group, X and Y, respectively, to generate the ketene complex. The ketene complexes III and V are highly electrophilic; thus, they are susceptible to nucleophilic attack. When a ketene is treated with an alcohol of the present invention, the alcohol reacts at C1 of the ketene to produce the corresponding ester (eq. 1). In another embodiment, an alkoxide will react with the ketene to generate the ester. In the present invention, the ketene complexes III and V are not isolated, but generated in situ prior to the addition of the alcohol. 
The bases useful for generating the ketene complexes of the present invention include, but are not limited to, an amide, a secondary amine or a tertiary amine. An amide is defined herein as (R)2Nxe2x8ax96, wherein each R is preferably an aliphatic group, a cycloaliphatic group, or a silyl group. Examples of amides useful in the present invention include, but are not limited to, potassium hexamethyldisilazide, sodium hexamethyldisilazide, lithium diisopropylamide, lithium hexamethyldisilazide, and lithium 2,2,6,6-tetramethylpiperidine. An examples of a secondary amine includes, but is not limited to, 2,2,6,6-tetramethylpiperidine. Examples of tertiary amines include, but are not limited to, dimethyl ethyl amine, triethylamine and pyridine.
One advantage of the present invention is that the stereochemistry at C2 of compounds I and IV does not have to be set. Thus, the stereochemistry at C2 can be S or R. When I-trans and I-cis are treated with a base (Scheme I), deprotonation at C2 and subsequent loss of X results in the formation of the ketene complex III. Thus, the applicants have discovered that the cis and trans isomers of I and IV can be used to esterify an alcohol, which is highly desirable and nowhere taught, suggested or otherwise motivated in the art. 
Another advantage of the present method is that once the ketene complexes III and V are generated, nucleophilic attack by the alcohol or alkoxide can occur diasteroselectively. In one embodiment, in the case of the acyclic ketene complex V, nucleophilic attack by the alcohol or alkoxide will most likely occur opposite or anti to the adjacent R group at Cb of V. In another embodiment, in the case of the cyclic ketene complex III, nucleophilic attack by the alcohol or alkoxide can occur anti or syn to the adjacent R group at Ca; however, due to thermodynamic considerations, the trans ester is the predominant product formed. Thus, by varying the stereochemistry at Ca and Cb, it is possible to generate optically active esters using this method of the present invention. This feature of the present invention is very useful with respect to the synthesis of biologically active compounds that possess ester groups.
In one embodiment, a compound having the structure I can be used to esterify an alcohol. In the case of compound I, R1 and R2 are, independently, from C1 to C12 branched or straight chain alkyl or substituted or unsubstituted aryl; and X is a halogen or OR3, wherein R3 is from C1 to C12 branched or straight chain alkyl; substituted or unsubstituted aryl; aralkyl; acyl, or S(O)2R41, wherein R41 is C1 to C12 branched or straight chain alkyl or substituted or unsubstituted aryl. Throughout the application, the alkyl group is from C1 to C12 branched or straight chain alkyl, preferably from C1 to C6 branched or straight chain alkyl, and more preferably from C1 to C4 branched or straight chain alkyl. The term xe2x80x9cacylxe2x80x9d is defined as a group having the structure Rxe2x95x90(O)CO, wherein Rxe2x95x90 is alkyl, aryl, or aralkyl. Acyl groups useful in the present invention include, but are not limited to, acetyl and benzoyl. The term xe2x80x9caralkylxe2x80x9d is defined as any group that has one or more aliphatic or cycloaliphatic groups attached to an aromatic ring. Examples of an aralkyl group of the present invention include, but are not limited to, benzyl and p-nitrobenzyl groups. In one embodiment, R1 and R2 are phenyl; R3 is methyl; and the stereochemistry at a is S. In another embodiment, R1 and R2 are phenyl; R3 is isopropyl; and the stereochemistry at a is S. In yet another embodiment, R1 and R2 are phenyl; R3 is tert-butyl; and the stereochemistry at a is S.
The invention further relates to a method for preparing a compound having the structure I: 
wherein,
R1 and R2 are, independently, from C1 to C12 branched or straight chain alkyl or substituted or unsubstituted aryl; and
X is OR3, wherein R3 is from C1 to C12 branched or straight chain alkyl; substituted or unsubstituted aryl; aralkyl; acyl, or S(O)2R41, wherein R41 is C1 to C12 branched or straight chain alkyl; or substituted or unsubstituted aryl, and
R2 and C(O)X are cis to one another,
comprising:
(a) admixing a compound having the structure VI: 
xe2x80x83wherein,
R1 and R2 are, independently, from C1 to C12 branched or straight chain alkyl or substituted or unsubstituted aryl;
X is OR3, wherein R3 is from C1 to C12 branched or straight chain alkyl; substituted or unsubstituted aryl; aralkyl; acyl, or S(O)2R41, wherein R41 is C1 to C12 branched or straight chain alkyl or substituted or unsubstituted aryl; and
the hydroxyl group and amide group are cis to one another, with a cyclization agent.
The applicants have discovered a method for preparing a compound having the structure I, wherein R2 and C(O)X are cis to one another. The cis and trans isomers of compound I are shown in Scheme I. The art heretofore only disclosed a method for making the trans isomer of compound I.
The use of a cyclization agent is necessary to cyclize compound VI to compound I. An example of a cyclization agent useful in the present invention is triflic anhydride with pyridine. Experimental conditions for the production of I via the cyclization of VI are outlined in the forthcoming examples.
The invention further relates to a compound having the formula I: 
wherein,
R1 and R2 are, independently, from C1 to C12 branched or straight chain alkyl or substituted or unsubstituted aryl;
X is OR3, wherein R3 is halogen; C1 to C12 branched or straight chain alkyl; substituted or unsubstituted aryl; aralkyl; acyl, or S(O)2R41, wherein R41 is C1 to C12 branched or straight chain alkyl; or substituted or unsubstituted aryl; and
R2 and C(O)X are cis to one another.
Compounds having the structure I, wherein the compound is the cis isomer, are not disclosed in the art. In one embodiment, R1 and R2 are phenyl; R3 is methyl; and the stereochemistry at a is S. In another embodiment, R1 and R2 are phenyl; R3 is tert-butyl; and the stereochemistry at a is S. In another embodiment, R1 and R2 are phenyl; R3 is isopropyl; and the stereochemistry at a is S. In another embodiment, R1 and R2 are phenyl; R3 is phenyl; and the stereochemistry at a is S. In another embodiment, R1 and R2 are phenyl; R3 is 2,3-dimethyl propyl, wherein the stereochemistry at the 2-position is S; and the stereochemistry at a is S.
In another embodiment, compound IV can be used to esterify an alcohol. In this case, R9 and R10 are, independently, an aralkyl or C(O)R31, wherein R31 is C1 to C12 straight chain or branched alkyl; substituted or unsubstituted aryl; or aralkyl; R11 is from C1 to C12 branched or straight chain alkyl or substituted or unsubstituted aryl; R12 is silyl; alkyl; aryl; acyl; or aralkyl; and Y is a halogen or OR13, wherein R13 is from C1 to C12 branched or straight chain alkyl or substituted or unsubstituted aryl, acyl, aralkyl or S(O)2R42, wherein R42 is C1 to C12 branched or straight chain alkyl or substituted or unsubstituted aryl. In one embodiment, R9 is benzyl; R10 is xcex1-methyl benzyl; R11 is phenyl; R12 is C(O)Ph; R13 is tert-butyl; and the stereochemistry at b is S. In another embodiment, R9 is benzyl; R10 is xcex1-methyl benzyl; R11 is phenyl; R12 is C(O)Ph; R13 is methyl; and the stereochemistry at b is S. In yet another embodiment, R9 is benzyl; R10 is xcex1-methyl benzyl; R11 is phenyl; R12 is C(O)Ph; Y is chloride; and the stereochemistry at b is S. As described above, the stereochemistry at C2 does not have to be set; therefore, NR9R10 and OR12 can be syn or anti to one another.
The invention further relates to a method for preparing a compound having the structure IV: 
wherein,
R9 and R10 are aralkyl;
R11 is substituted or unsubstituted aryl;
R12 is acyl, silyl, alkyl, aryl, or aralkyl; and
Y is OR13, wherein R13 is from C1 to C12 branched or straight chain alkyl or substituted or unsubstituted aryl, acyl, aralkyl or
S(O)2R42, wherein R42 is C1 to C12 branched or straight chain alkyl or substituted or unsubstituted aryl,
comprising:
(a) admixing a base and a compound having the structure IX: 
xe2x80x83wherein,
R9 and R10 are aralkyl;
R11 is substituted or unsubstituted aryl; and
Y is OR13, wherein R13 is from C1 to C12 branched or straight chain alkyl; or substituted or unsubstituted aryl, acyl, aralkyl, or S(O)2R42, wherein R42 is C1 to C12 branched or straight chain alkyl; or substituted or unsubstituted aryl,
to produce an intermediate, and
(b) admixing the intermediate of step (a) with an esterification agent, a silylating agent, or an alkylating agent.
Treatment of compound IX with a base results in deprotonation of the hydroxyl proton to generate the corresponding alkoxide. The alkoxide is referred to as the intermediate recited above. The alkoxide is not isolated, but subsequently treated with an esterification agent, a silylating agent, or an alkylating agent to produce compound IV. The term xe2x80x9cesterification agentxe2x80x9d is defined as any agent that will react with an alkoxide to produce an ester. Examples of esterification agents useful in the present invention include, but are not limited to, organic anhydrides and acyl halides. In one embodiment, the esterification agent is benzoyl chloride.
The base employed is any compound capable of deprotonating a hydroxyl group. Bases used to generate the ketene compounds III and V, such as amides, secondary and tertiary amines, are suitable for deprotonation of the hydroxyl group of IX. In one embodiment, triethyl amine can be used as the base. The experimental conditions for preparing compound IV are presented in the forthcoming examples.
The invention further relates to a compound having the structure IV: 
wherein,
R9 and R10 are aralkyl;
R11 is substituted or unsubstituted aryl;
R12 is acyl, silyl, alkyl, aryl or aralkyl; and
Y is a halogen or OR13, wherein R13 is from C1 to C12 branched or straight chain alkyl or substituted or unsubstituted aryl, acyl, aralkyl, or S(O)2R42, wherein R42 is C1 to C12 branched or straight chain alkyl; or substituted or unsubstituted aryl.
In one embodiment, R9 is benzyl; R10 is -methyl benzyl; R11 is phenyl; R12 is C(O)Ph; and Y is tert-butoxy. In another embodiment, R9 is benzyl; R10 is -methyl benzyl; R11 is phenyl; R12 is C(O)Ph; and Y is methoxy.
Once the ketene complexes III and V have been generated, the addition of an alcohol or an alkoxide will result in the formation of an ester. The applicants have discovered that a wide variety of alcohols can be added to the ketene compounds III and V to produce the corresponding ester. Alcohols useful in the present invention include, but are not limited to, aliphatic alcohols, aromatic alcohols, cycloaliphatic alcohols, or heteroaromatic alcohols. In a preferred embodiment, the alcohol is a cycloaliphatic alcohol. In another embodiment, the alcohol is (2S)-hydroxy-3-methylbutane.
In another preferred embodiment, the alcohol is a compound having the structure II: 
wherein,
R4 is acetyl or hydrogen;
R5 is hydrogen;
R6 is benzoyl;
R7 is acetyl; and
R8 is hydrogen, SiEt3 or C(O)CH2CCl3.
As described above, it is advantageous to efficiently attach a side chain to the hydroxyl group at the C-13 position of baccatin and derivatives thereof. In one embodiment, for compound II, R4 and R5 are hydrogen; R6 is benzoyl; R7 is acetyl; and R8 is hydrogen, SiEt3 or C(O)CH2CCl3. This alcohol is the precursor to taxotere. In another embodiment, R4 and R7 are acetyl; R5 is hydrogen; R6 is benzoyl; and R8 is hydrogen, SiEt3 or C(O)CH2CCl3. This alcohol is the precursor to Taxol.
The invention further relates a compound having the structure XIV or XV: 
wherein,
R44 and R45 are, independently, hydrogen; C1-C12 branched or straight chain alkyl; or R44 and R45 are part of a cycloaliphatic group;
when g is a single bond, R46 is hydroxy; acetyl; or C1-C12 branched or straight chain alkoxy;
when g is a double bond, R46 is oxygen;
R47 is a C1-C12 branched or straight chain alkyl ester; C1-C12 branched or straight chain alkyl; carboalkoxy; hydroxyalkyl; or derivatized or protected hydroxyalkyl;
R48 is C1-C12 branched or straight chain alkyl; substituted or unsubstituted aryl; acetyl; hydroxyalkyl; or derivatized or protected hydroxyalkyl;
R49 and R50 are, independently, hydrogen; C1-C12 branched or straight chain alkyl or alkoxy; or acetyl, provided that when one of R49 or R50 is hydrogen, the other of R49 and R50 is not hydrogen;
when m is a double bond, R51 is oxygen;
when m is a single bond, R51 is OH or OC(O)R52, wherein R52 is substituted or unsubstituted aryl; or cycloaliphatic; and
the hydroxyl group is located at carbon h or i.
Applicants have discovered that compounds having the structure XIV and XV are structurally simplified analogs of Taxol with incorporated structural elements of Taxol which can embody Taxol""s biological activity. Due to the difficulty in synthesizing Taxol, simplified analogs could be advantageous over semi-synthetic analogs of Taxol. The hydroxy group can be positioned at either carbon h or i, and the stereochemistry at these positions can be either R or S. In one embodiment, the hydroxyl group is at carbon h, and the stereochemistry at carbon h is S. In another embodiment, the hydroxyl group is at carbon h, and the stereochemistry at carbon h is R. In another embodiment, the hydroxyl group is at carbon i, and the stereochemistry at carbon i is S. In another embodiment, the hydroxyl group is at carbon i, and the stereochemistry at carbon i is R.
In another embodiment, R44 and R45 of compounds XIV and XV are independently, hydrogen or methyl, preferably hydrogen and methyl. In another embodiment, R44 and R45 are part of a cycloaliphatic group, wherein the cycloaliphatic group can be cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In one embodiment, the cycloaliphatic group is a cyclopropyl group. In another embodiment, R47 is methyl ester or methyl. In another embodiment, R48 is hydroxy, ethoxy, propoxy, or derivatized or protected hydroxy. The term xe2x80x9cderivatized or protected hydroxyxe2x80x9d refers to hydroxyl group that has been converted to a alkoxy group, an aryloxy group, an aralkoxy group, an acyloxy group or a silyloxy group. In another embodiment, m is a single bond and R52 is phenyl or cyclohexyl.
In one embodiment, when the compound has the structure XIV, R44 and R45 are hydrogen; g is a double bond; R47 is C(O)OMe; the stereochemistry at carbon p is R; R48 is methyl; the stereochemistry at carbon k is S; R48 is methyl; R49 is methyl; the stereochemistry at carbon q is R; R50 is hydrogen; the stereochemistry at carbon r is S; m is a single bond; R51 is OC(O)Ph; the stereochemistry at carbon j is R; and the hydroxyl group is at carbon h or i. In another embodiment, the hydroxyl group is at carbon h and the stereochemistry at carbon h is R. In another embodiment, the hydroxyl group is at carbon h and the stereochemistry at carbon h is S. In another embodiment, the hydroxyl group is at carbon i and the stereochemistry is S.
In one embodiment, when the compound has the structure XIV, R44 and R45 are hydrogen; g is a double bond; R47 is C(O)OMe; the stereochemistry at carbon p is R; R48 is methyl; the stereochemistry at carbon k is S; R49 is methyl; the stereochemistry at carbon q is R; R50 is hydrogen; the stereochemistry at carbon r is S; m is a double bond; and the hydroxyl group is at carbon h or i. In another embodiment, the hydroxyl group is at carbon h and the stereochemistry at carbon h is R. In another embodiment, the hydroxyl group is at carbon h and the stereochemistry at carbon h is S. In another embodiment, the hydroxyl group is at carbon i and the stereochemistry at carbon i is S.
Procedures for preparing compounds XIV and XV are provided in the forthcoming examples. Using the process of the present invention, compounds XIV and XV can be used to esterify alcohols.
In another embodiment, the corresponding alkoxide of the alcohols described above will also generate an ester when used in the process of the present invention. Any base that is capable of deprotonating a hydroxyl proton to produce the corresponding oxide anion is suitable in the present invention. Bases useful in the present invention include, but are not limited to, potassium hexamethyldisilazide, sodium hexamethyldisilazide, triethylamine, lithium diisopropylamide, lithium hexamethyldisilazide, dimethylethylamine, potassium hydride, sodium hydride or lithium 2,2,6,6-tetramethylpiperidine.
The present invention also provides a process for the esterification of an alcohol and/or an alkoxide that does not require the use of harsh reaction conditions (i.e. elevated temperature, extended reactions times). In one embodiment, the base is initially added to compound I or IV prior to the addition of the alcohol or alkoxide. In one embodiment, the amount of base used is less than the amount of compound I or IV. In a preferred embodiment, an excess amount of base is used relative to the amount of compound I or IV. In the case of compound I, the amount of base employed is from 1 to 10 equivalents, preferably 1 to 1.5 equivalents to 1 equivalent compound I. In another embodiment, when compound IV is used, the amount of base used is from 1 to 10 equivalents to 1 equivalent of compound IV. A slight excess of base relative to compounds I and IV is necessary in order to generate the corresponding ketene prior to the addition of the alcohol or alkoxide.
The process of the present invention typically involves the use of a solvent system. Organic solvents known in the art are useful in the present invention. Examples of organic solvents useful in the present invention include, but are not limited to, tetrahydrofuran, diethyl ether, toluene, dimethoxyethane, t-butyl methyl ether, or a mixture thereof.
Reaction temperatures and times can vary when adding the base to compounds I and IV. In one embodiment, the base is added to compound I from xe2x88x9250xc2x0 C. to 80xc2x0 C. In another embodiment, the lower limit of the reaction temperature is xe2x88x9245xc2x0 C., xe2x88x9240xc2x0 C., xe2x88x9235xc2x0 C., xe2x88x9230xc2x0 C., xe2x88x9225xc2x0 C., xe2x88x9220xc2x0 C., or xe2x88x9215xc2x0 C., and the upper limit is xe2x88x925xc2x0 C., xe2x88x9210xc2x0 C., xe2x88x9215xc2x0 C., xe2x88x9220xc2x0 C., xe2x88x9225xc2x0 C., 0xc2x0 C., 20xc2x0 C., 40xc2x0 C., or 60xc2x0 C. The base is allowed to react with compound I or IV at from 30 seconds to 3 hours. In another embodiment, the lower time limit can be 1, 5, 10, 15 minutes, and the upper limit can be 2 hours, 1 hour, 30 minutes, 15 minutes, 10 minutes, or 5 minutes.
Once the ketene complexes III and V have been generated in situ, an alcohol, alkoxide, or a combination thereof is added. The amount of the alcohol or alkoxide can be from 1 to 3 equivalents, preferably from 1 to 2 equivalents, and more preferably from 1 to 1.2 equivalents. The alcohol or alkoxide is allowed to react with the ketene at from 15 minutes to 24 hours, preferably from 15 minutes to 2 hours. In another embodiment, the lower time limit can be 20, 25, 30, 40 or 50 minutes, and the upper limit can be 1 hour, 45 minutes; 1 hour, 30 minutes; 1 hour; or 45 minutes. The temperature at which the alcohol and/or alkoxide can be added to the ketene can be from xe2x88x9250xc2x0 C. to 23xc2x0 C. In another embodiment, the lower temperature limit can be xe2x88x9245xc2x0 C., xe2x88x9240xc2x0 C., xe2x88x9235xc2x0 C., xe2x88x9230xc2x0 C., xe2x88x9225xc2x0 C. or xe2x88x9220xc2x0 C.; and the lower limit can be 20xc2x0 C., 15xc2x0 C., 10xc2x0 C., 5xc2x0 C., 0xc2x0 C., xe2x88x925xc2x0 C. xe2x88x9210xc2x0 C. or xe2x88x9220xc2x0 C.
Esterification of Alcoholsxe2x80x94Part II
In accordance with the purpose(s) of this invention, as embodied and broadly described herein, this invention, in one aspect, relates to a method for preparing an ester, comprising admixing a compound having the structure VII: 
wherein,
R15 and R16 are, independently, hydrogen, Si(R21)3 or C(O)R22, wherein each R21 is, independently, branched or straight chain C1-C12 alkyl; and R22 is substituted or unsubstituted aryl, aralkyl or from C1-C12 branched or straight chain alkyl;
R17 is substituted or unsubstituted aryl, aralkyl, or from C1-C12 branched or straight chain alkyl;
R18 is hydrogen; branched or straight chain C1-C12 alkyl; unsubstituted or substituted aryl; aralkyl; Si(R28)3 or C(O)R29, wherein, each R28 is, independently, branched or straight chain C1-C12 alkyl; or aralkyl;
R29 is substituted or unsubstituted aryl, aralkyl or from C1-C12 branched or straight chain alkyl;
R19 and R20 are, independently, branched or straight chain C1-C12 alkyl, aryl, aralkyl, or C(O)OR30, wherein R19 is not hydrogen;
R30 is branched or straight chain C1-C12 alkyl; and
V and W are, independently, sulfur, oxygen, or NR43, wherein R43 is hydrogen; branched or straight chain C1-C12 alkyl; or aralkyl,
with an alkoxide.
The alkoxide is prepared in situ by treating the corresponding alcohol with a base. Bases useful in generating the alkoxide include, but are not limited to amides, secondary and tertiary amines. In a preferred embodiment, lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, n-butyllithium, sodium hydride, potassium hydride or lithium diisopropylamide can be used. Once the alkoxide is produced, it can react with compound VII to generate an ester. Nucleophilic attack at the carbamide followed by the loss of the heterocyclic ring results in the formation of the ester.
The method of the present invention has a number of advantages. First, by varying the stereochemistry of R19 and R20 of compound VII, it is possible to control the diasteroselectivity of the condensation reaction between the alkoxide and compound VII. Second, by varying V and W of compound VII, it is possible to enhance or increase the reaction between the alkoxide and compound VII. In one embodiment, V and W are sulfur. In another embodiment, R17 is phenyl and R18 is benzoyl. Finally, it is possible to recover the oxazolidine ring and reuse it after the condensation reaction.
All of the alcohols described above can be converted to the corresponding alkoxide and used in the present invention. In one embodiment, the alkoxide is a compound having the structure VIII: 
wherein,
R23 is acetyl or hydrogen;
R24 is hydrogen;
R25 s is benzoyl;
R26 is acetyl; and
R27 is hydrogen, SiEt3 or C(O)CH2CCl3.
As described above, an efficient method for attaching a side chain at the C-13 position of baccatin or derivatives thereof is not known in the art; thus, the applicants have discovered another method for attaching a side chain to precursors of taxol and derivatives thereof. In one embodiment, for compound VIII, R23 and R24 are hydrogen; R25 is benzoyl; R26 is acetyl; and R27 is hydrogen, SiEt3 or C(O)CH2CCl3. This alkoxide is the precursor to taxotere. In another embodiment, R23 and R26 are acetyl; R24 is hydrogen; R25 is benzoyl; and R27 is hydrogen, SiEt3 or C(O)CH2CCl3. This alkoxide is a precursor to Taxol.
In another embodiment, the alkoxide is a compound having the structure XVI or XVII: 
wherein,
R44 and R45 are, independently, hydrogen; C1-C12 branched or straight chain alkyl; or R44 and R45 are part of a cycloaliphatic group;
when g is a single bond, R46 is hydroxy; acetyl; or C1-C12 branched or straight chain alkoxy;
when g is a double bond, R46 is oxygen;
R47 is a C1-C12 branched or straight chain alkyl ester; C1-C12 branched or straight chain alkyl; carboalkoxy; hydroxyalkyl; or derivatized or protected hydroxyalkyl;
R48 is C1-C12 branched or straight chain alkyl; substituted or unsubstituted aryl; acetyl; hydroxyalkyl; or derivatized or protected hydroxyalkyl;
R49 and R50 are, independently, hydrogen; C1-C12 branched or straight chain alkyl or alkoxy; or acetyl, provided that when one of R49 or R50 is hydrogen, then the other of R49 and R50 is not hydrogen;
when m is a double bond, R51 is oxygen;
when m is a single bond, R51, is OC(O)R52, wherein R52 is substituted or unsubstituted aryl; or cycloaliphatic; and
the hydroxyl group is located at carbon h or i.
The invention further relates to a compound having the structure VII: 
wherein,
R15 and R16 are, independently, hydrogen, Si(R21)3 or C(O)R22, wherein each R21 is, independently, branched or straight chain C1-C12 alkyl; and
R22 is substituted or unsubstituted aryl, aralkyl or from C1-C12 branched or straight chain alkyl;
R17 is substituted or unsubstituted aryl, aralkyl, or from C1-C12 branched or straight chain alkyl;
R18 is hydrogen; branched or straight chain C1-C12 alkyl; unsubstituted or substituted aryl; aralkyl; Si(R28)3 or C(O)R29, wherein,
each R28 is, independently, branched or straight chain C1-C12 alkyl; or aralkyl;
R29 is substituted or unsubstituted aryl, aralkyl or from C1-C12 branched or straight chain alkyl;
R19 and R20 are, independently, branched or straight chain C1-C12 alkyl, aryl, aralkyl, or C(O)OR30, wherein R19 is not hydrogen;
R30 is branched or straight chain C1-C12 alkyl; and
V and W are, independently, sulfur, oxygen, or NR43, wherein R43 is hydrogen; branched or straight chain C1-C12 alkyl; or aralkyl.
The invention further relates to a method for preparing a compound having the structure VII: 
wherein,
R15 and R16 are, independently, hydrogen, Si(R21)3 or C(O)R22, wherein each R21 is, independently, branched or straight chain C1-C12 alkyl; and R22 is substituted or unsubstituted aryl, aralkyl or from C1-C12 branched or straight chain alkyl;
R17 is substituted or unsubstituted aryl, aralkyl, or from C1-C12 branched or straight chain alkyl;
R18 is branched or straight chain C1-C12 alkyl; unsubstituted or substituted aryl; aralkyl; Si(R28)3 or C(O)R29, wherein,
each R28 is, independently, branched or straight chain C1-C12 alkyl; or aralkyl;
R29 is substituted or unsubstituted aryl, aralkyl or from C1-C12 branched or straight chain alkyl;
R19 and R20 are, independently, branched or straight chain C1-C12 alkyl, aryl, aralkyl, or C(O)OR30, wherein R19 is not hydrogen;
R30 is branched or straight chain C1-C12 alkyl; and
V and W are, independently, sulfur, oxygen, or NR43, wherein R43 is hydrogen; branched or straight chain C1-C12 alkyl; or aralkyl,
comprising,
(a) admixing
(i) a compound having the structure X 
wherein R18-R20 are as above,
(ii) a Lewis acid; and
(iii) a base,
to produce a first intermediate;
(b) reacting the first intermediate of step (a) with a compound having the structure XI: 
wherein R15 and R17 are as above,
to produce a second intermediate; and
(c) admixing the second intermediate of step (b) with a proton source.
Treatment of compound X with a Lewis acid and a base results in the formation of an enolate, which is the first intermediate recited above. In one embodiment, compound X is treated with the Lewis acid prior to the addition of the base. Bases useful for generating the enolate include, but are not limited to, potassium hexamethydisilazide, sodium hexamethydisilazide and lithium diisopropylamide. In a preferred embodiment, the base is lithium diisopropylamide. Once the enolate has been prepared in situ, it is treated with the imine compound XI. In a preferred embodiment, R15 of the imine is C(O)Ph. The enolate reacts with the imine to generate a xcex2-amino, xcex1-alkoxyamide, which is the second intermediate recited above. In another embodiment, the Lewis acid facilitates the reaction between the enolate and the imine. In one embodiment, the Lewis acid is a zinc, magnesium, aluminum, boron, tin or titanium compound. In another embodiment, the Lewis acid comprises a dialkylboron triflate, stannous triflate, stannic chloride, stannous chloride or titanium tetrachloride.
Once the xcex2-amino, xcex1-alkoxyamide is produced, it is quenched with a proton source. Proton sources useful in the present invention include, but are not limited to, a weak acid or water.
The invention further relates to a method for preparing a compound having the structure VII: 
wherein,
R15 and R16 are, independently, hydrogen, Si(R21)3 or C(O)OMe, wherein each R21 is, independently, branched or straight chain C1-C12 alkyl; and R22 is substituted or unsubstituted aryl, aralkyl or from C1-C12 branched or straight chain alkyl;
R17 is substituted or unsubstituted aryl, aralkyl, or from C1-C12 branched or straight chain alkyl;
R18 is hydrogen;
R19 and R20 are, independently, branched or straight chain C1-C12 alkyl, aryl, aralkyl, or C(O)OR30, wherein R19 is not hydrogen;
R30 is branched or straight chain C1-C12 alkyl; and
V and W are, independently, sulfur, oxygen, or NR43, wherein R43 is hydrogen; branched or straight chain C1-C12 alkyl; or aralkyl,
comprising,
(a) admixing
(i) a compound having the structure XIII 
wherein R19-R20 and R22 are as above,
(ii) a Lewis acid; and
(iii) a first base,
to produce a first intermediate;
(b) reacting the first intermediate of step (a) with a compound having the structure XI: 
wherein R15 and R17 are as above,
to produce a second intermediate; and
(c) admixing the second intermediate with a basic buffer, wherein the buffer comprises a second base.
In a similar reaction as described above, the addition of a first base, such as an amide or secondary or tertiary amine, to compound XIII results in the formation of an enolate, which is the first intermediate recited above. Once the enolate has been produced, the imine compound XI is added to produce an xcex2-amino, xcex1-alkoxyamide, which is the second intermediate. The amide is then treated with a basic buffer to generate compound VII. In one embodiment, the buffer is an aqueous solution of NaHCO3 or a phosphate. Upon treatment of the amide intermediate with the basic buffer, the C(O)R22 group migrates from oxygen to nitrogen. The migration of C(O)R22, and in particular, C(O)Ph, from oxygen to nitrogen under basic conditions is well known in the art.